EP0630381A1 - Derives acycliques antiviraux alcenyle et alkynyle de purine et de pyrimidine substitues par phosphonomethoxyalkyle. - Google Patents

Derives acycliques antiviraux alcenyle et alkynyle de purine et de pyrimidine substitues par phosphonomethoxyalkyle.

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Publication number
EP0630381A1
EP0630381A1 EP92922088A EP92922088A EP0630381A1 EP 0630381 A1 EP0630381 A1 EP 0630381A1 EP 92922088 A EP92922088 A EP 92922088A EP 92922088 A EP92922088 A EP 92922088A EP 0630381 A1 EP0630381 A1 EP 0630381A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
azido
phosphonomethoxy
guanine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP92922088A
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German (de)
English (en)
Other versions
EP0630381A4 (en
EP0630381B1 (fr
Inventor
John C Martin
Joanne J Bronson
Kuo-Long Yu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Stichting Rega VZW
Czech Academy of Sciences CAS
Institute of Organic Chemistry and Biochemistry CAS
Original Assignee
Stichting Rega VZW
Czech Academy of Sciences CAS
Institute of Organic Chemistry and Biochemistry CAS
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Publication of EP0630381A1 publication Critical patent/EP0630381A1/fr
Publication of EP0630381A4 publication Critical patent/EP0630381A4/en
Application granted granted Critical
Publication of EP0630381B1 publication Critical patent/EP0630381B1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • This invention concerns nucleotide analogs, their method of preparation and their compositions and use in the treatment of viral infections.
  • it concerns acyclic phosphonomethoxyalkylsubstituted, alkenyl and alkynyl derivatives of purine and pyrimidine bases.
  • nucleoside analogs are nucleoside analogs. In general, these compounds are structural analogs of the naturally occurring nucleoside analogs.
  • saccharide component results in a synthetically modified nucleoside derivative which, when incorporated into a viral nucleic acid forming process, acts to disrupt further synthesis of viral nucleic acid.
  • Effectiveness of these antiviral agents depends on selective conversion by viral enzymes or by host enzymes, to the corresponding nucleotide analog which is then converted to the triphosphate and incorporation into viral nucleic acid occurs.
  • a problem with this antiviral strategy has been the emergence of certain viral strains whose enzymes poorly promote phosphorylation of the nucleoside analogs. To circumvent this problem, intact nucleotide analogs appear to be potentially quite useful as antivirals for incorporation into viral nucleic acid.
  • B is a purine or
  • ⁇ -pentofuranose sugar or R 1 is H and R 2 is H or
  • R 3 is H or OH
  • X is H, OH or together with Y is carbonyl oxygen and Y can also be H
  • Z 1 and Z 2 are H or alkyl.
  • the ether-oxygen link to the carbon atom attached to the base which is intended to preserve or mimic the acetal oxygen bond of a pentofuranose sugar ring; and 2) the phosphate modification is a phosphonoalkylene moiety.
  • the acyclic sugar analog component of the instant compounds is comprised of an all carbon atom backbone up to a phosphonomethoxy moiety.
  • R 2 and R 3 are H or together complete a ribonucleoside ring; and both R 4 are
  • B denotes a purine-9-yl.
  • Formula 6 shows selective antiretroviral activity.
  • Phosphonomethoxyalkenyl and azidoalkyl purine and pyrimidine derivatives have been synthesized and found to possess useful antiviral activity.
  • the alkynyl derivatives of purine and pyrimidine can be prepared by following the same synthetic sequence which is used for the preparation of the alkenyl derivatives.
  • aminoalkyl derivatives can be prepared by reduction of the corresponding azidoalkyl derivatives.
  • B is a purine or pyrimidine base
  • R is straight alkyl substituted by azido or amino, wherein the alkyl is from 1-2 carbon atoms, straight or branched alkenyl or alkynyl of 2-6 carbon atoms.
  • Other aspects of this invention involve preparation of these compounds, their formulation into pharmaceutical compositions and the use of these formulations to treat viral infections in mammals including humans and in particular, those caused by HIV.
  • B is a purine or pyrimidine base selected from the group consisting of adenine, xanthine, hypoxanthine, guanine, 8-bromoguanine, 8-chloroguanine, 8-aminoguanine, 8-hydrazinoguanine, 8-hydroxyguanine, 8-methylguanine, 8-thioguanine, 2-aminopurine,
  • 2,6-diaminopurine 2,6-diaminopurine, thymine, cytosine, uracil, 5-bromouracil, 5-iodouracil, 5-ethyluracil,
  • R is a straight alkyl substituted by azido or amino, wherein the alkyl is from 1-2 carbon atoms, straight or branched alkenyl of 2-6 carbon atoms or a straight or branched alkynyl of 2-6 carbon atoms, the monoester, diester and the corresponding salt, hydrate, solvate, the R or S isomer and the racemic mixture (RS) thereof, with the proviso that when R is azidomethyl or aminomethyl, then B is not adenine and when R is (S) azidomethyl, then B is not thymine and when R is (S) azidoethyl, then B is not guanine.
  • alkyl of 1-2 carbons which are substituted by amino or azido are:
  • alkenyl of 2-6 carbon atoms examples are:
  • -CH 2 -CH CH-CH 2 CH 2 CH 3
  • -CH 2 -CH 2 -CH CH-CH 3
  • the monoesters and the diesters are of alkanol of 1-5 carbon atoms, as, for example, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, etc.
  • the preferred phosphonate moiety are the monoester and the acid.
  • the salts are pharmaceutically acceptable non-toxic salts.
  • physiologically acceptable salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with the acid anion moiety of the phosphonic acid group.
  • salts may be formed from acid addition of certain organic and inorganic acids with basic centers of purines and
  • pyrimidines Such acids are, for example, HCl, HBr,
  • metal salts Li + , K + , Na + , Ca ++ and Mg ++ .
  • the compounds of the present invention can exist in various tautomeric forms, in their unionized as well as zwitterionic form and/or in the form of solvates and hydrates, which are to be included within the scope of the present invention.
  • solvates are methanolate, ethanolate, propanolate, iso-propanolate, butanolate, etc.
  • hydrates are monohydrate, dihydrate, trihydrate, etc.
  • the compounds of the present invention can exist as optical isomers and both racemic (RS) and the individual chiral isomers R or S are all within the scope of the invention.
  • the preferred isomer is R, which unexpectedly exhibits complete cell protection against HIV over a broad concentration range with no observable cytotoxicity.
  • the preferred compounds of Formula I are those wherein B is guanine, adenine, uracil, cytosine or thymine and R is a straight alkyl of 1-2 carbon atoms which is substituted by azido or amino, straight alkenyl or alkynyl of 2-3 carbon atoms.
  • the most preferred compounds of Formula I are those wherein B is guanine, adenine, uracil, cytosine or thymine and R is CH 2 N 3 ,
  • the compounds of Formula I namely, the (R) and (S) chiral isomers can be prepared by a stero-specific synthesis, beginning with the appropriate enantiomeric
  • reaction scheme 1 for the (R) isomer.
  • the (S) isomer can be prepared following the reaction scheme 1, except for the use of opposite enantiomeric (chiral) starting material.
  • the (R) and (S) chiral isomers can also be prepared by resolving the racemic mixture (RS) through well-known techniques, for example, the separation of diastereomeric salts formed with optically active
  • the racemic mixture (RS) can be prepared using the reaction scheme 1, except for the use of the racemic starting material.
  • 1,2-propanediol of Formula II can be synthesized
  • MMT-Cl p-anisylchlorodiphenylmethane
  • the reaction can be carried out with methylsulfonyl chloride and triethylamine to produce the corresponding mesylate.
  • the condensation of purine or pyrimidine base can be carried out in a coupling reaction with the mesylate in an inert organic solvent such as acetonitrile, dimethylformamide and the like in the presence of an excess of inorganic bases such as cesium carbonate or sodium hydride to produce the compound of Formula IV.
  • the compound of Formula IV may be first treated with bromotrimethylsilane to give the
  • (R)-isomer of Formula I The compound of Formula IV can be hydrolyzed with alkali to give the corresponding monoesters of Formula V.
  • the preparation of the chiral (S)-isomer of Formula I starts with the (S)-1,2-propanediol which is commercially available or can be synthesized following procedures known in the art with commercially available starting materials.
  • the optically active (S)-isomer of Formula I can be prepared from the primary alcohol following the same general procedures and reaction sequences as illustrated in reaction scheme 1 for the preparation of the (R)-isomer of Formula I.
  • racemic mixture (RS) of the compound of Formula I can be prepared following the same general procedures and reaction sequences as illustrated in reaction scheme 1 for the preparation of the (R)-isomer of Formula I, but starting with the racemic (RS) 1,2-propanediol of Formula II.
  • the compound of Formula XIV is converted to the mesylate of Formula XV with mesyl chloride in the presence of triethylamine and an inert organic solvent, such as methylene chloride.
  • the mesylate of Formula XV is then coupled with a purine or pyridine base, for example, guanine or cytosine in an inert organic solvent such as acetonitrile,
  • optically active (R) chiral isomer of the compound of Formula I when R is vinyl is prepared from the starting material chiral (R)-1,2,4-butane triol and following the same general procedures and reaction sequences as illustrated in reaction scheme 2, for the preparation of the (S)-vinyl isomer.
  • R optically active
  • the racemic mixture (RS) for the compound of Formula I, when R is vinyl can be prepared from the starting material (RS)-1,2,4-butane triol and following the procedures and reactions as illustrated in reaction scheme 2, for the preparation of the (S)-vinyl isomer.
  • the racemic mixture (RS) for the compound of Formula I, when R is vinyl can also be resolved into the (R) and (S) isomer by methods well-known in the art.
  • (RS)-1,2,4-butane triol can be prepared by methods well known in the art.
  • the (S) or (R) isomer of the aminomethyl compounds of Formulae XXVII or XXVIII or XXIX can be prepared by reduction of the corresponding (S) or (R) azidomethyl compounds of Formulae XXVII or XXVIII or XXIX.
  • salts of Formula I are prepared by methods known in the art.
  • the salts include ammonium salts and salts of physiologically acceptable metals, particularly Li + , K + , Na + , Ca ++ and Mg ++ , and comprise a further aspect of the invention.
  • Metal salts can be prepared by reacting the metal hydroxide with the Formula I compound of this invention. Examples of metal salts which can be prepared in this way are salts containing Li + , Na + and K + . A less soluble metal salt can be precipitated from the solution of a more soluble salt by the addition of the suitable metal compound.
  • Acid salts may be prepared by reacting a
  • Formula I compound with an inorganic or organic acid e.g., HCl, HBr, H 2 So 4 , organic sulfonic acids and the like.
  • the solvates and hydrates of the compound of Formula I can be prepared by crystallizing a compound of Formula I from solvents such as water, methanol, ethanol, etc.
  • Racemic-2'-vinyl-PMEG (RS)-9-[2-(phosphonomethoxy)
  • Racemic-2'-azido-PMEG (RS)-[3-azido-2- (phosphonomethoxy) propyl]guanine
  • the compounds of the instant invention and a known compound PMEG are presented in Table I and FIGS. 1-7, along with their relative cytotoxicities.
  • HIV RF strain obtained from Luc Montagnier, Institut Pasteur, Paris, France
  • Retroviruses 1987, 3, 283-302
  • XTT assay described by O. S. Weislow, et al., in J. Natl. Cancer Instit., 1989, 81, 577-586.
  • CEM-SS cells were obtained from Owen Weislow at the National Cancer Institute.
  • the optical density reading is
  • FIGS. 1-7 The relative optical density values were derived by dividing the sample observed optical density by the value obtained for the control. Assays run in infected cells show the antiviral effect of the test compounds, where an increase in the number of viable cells (higher OD reading) reflects the protective, antiviral activity of the compound. Assays run in uninfected cells provide a measure of cellular toxicity.
  • the antiviral effect is also expressed (see Table 1) as the concentration of compound which increases the number of viable cells in infected cultures to 50%, that of the untreated, uninfected control cultures (ED 50 ).
  • the cellular toxicity is expressed as the concentration of compound which reduces the number of viable cells to 50%, that of the untreated control (TD50).
  • selectivity index is the ratio of TD 50 to ED 50 .
  • the anti-HIV activity and cellular toxicity of the test compounds are plotted in FIGS. 1-7 as a function of relative optical density versus increasing log
  • FIGS. 1-7 visually show the results of the relative anti-HIV activity of the test compounds on infected cells (-O-) and the cellular toxicity of the same test compound on uninfected cells (---).
  • FIG. 7 The anti-HIV activity of the comparison compound PMEG is shown in FIG. 7 (CEM-SS cells).
  • the anti-HIV activity of (R)-2'-azidomethyl PMEG and (S)-2'-azidomethyl PMEG is shown in FIGS. 3 and 4.
  • the anti-HIV activity of the racemic (RS)-2'-vinyl PMEG and (RS)-2'-azidomethyl PMEG is shown in FIGS. 5 and 6.
  • FIG. 1 shows that, over a concentration range of 5 to 100 ⁇ M, (R)-2 , -vinyl-PMEG provides complete protection from the human immunodeficiency virus in CEM-SS cell lines with no observed cellular toxicity at concentrations less than 100 ⁇ M.
  • FIG. 1 shows that, over a concentration range of 5 to 100 ⁇ M, (R)-2 , -vinyl-PMEG provides complete protection from the human immunodeficiency virus in CEM-SS cell lines with no observed cellular toxicity at concentrations
  • selectivity index an in vitro "therapeutic index”
  • the selectivity index (SI) for (RS), (R)- and (S)-2'-vinyl-PMEG and (RS), (R), (S)-2 azidomethyl PMEG of the instant invention and for the comparison compound PMEG are shown in Table 1.
  • Table 1 The data in Table 1 clearly shows that (R)-2'-vinyl-PMEG and
  • Effective Dose 50 In infected cells, concentration of compound which results in an increase in the number of viable cells to 50% that of uninfected control.
  • the sample was prepared by mixing the (R) and (S) isomers in a 1 to 1 ratio.
  • the compound was evaluated by Southern Research Institute using human immunodeficiency virus HTLV-IIIB strain and MT-2 cells (S. Harada, et al., Science, 1985, 229, 563).
  • (R)-2'-azidomethyl PMEG 1400 *CC50 is the concentration of drug that causes a 50 percent decrease in cell count as compared to the control at day three (72 hours).
  • Protocol for the above assay is given below: 1. Choose proper range of the concentrations of the drug to be evaluated.
  • RPMI 1640 For cell control, 2 ml of RPMI 1640 is added in place of the drug solutions.
  • the concentration of drug that causes a 50 percent decrease of cell number as compared to the control at day three (72 hr) is assigned as the CC 50 value of the drug.
  • the invention accordingly, provides compounds of Formula I and their pharmaceutically acceptable salts and solvates thereof and, preferably, the compound of Formula I which is (R)-isomer and its pharmaceutically acceptable salts and solvates thereof for use in the therapy or prophylaxis of viral infections, especially human immunodeficiency virus, in a human subject.
  • the compounds of this invention including the pharmaceutically acceptable salts and solvates thereof, have desirable antiviral activity. They exhibit activity against retroviruses. In particular, the compound of Formula I exerts a significant anti-HIV effect with no observed cytotoxicity.
  • the compounds of this invention may be formulated into pharmaceutical preparations in any convenient way, and the invention, therefore, also includes, within its scope,
  • compositions comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof adapted for use in human medicine. Such compositions may be presented for use in conventional manner in admixture with one or more pharmaceutically acceptable carriers or excipients.
  • the compounds may be administered topically or systemically.
  • systemic administration is intended oral, rectal, and parenteral (i.e., intramuscular, intravenous, subcutaneous, and nasal) routes.
  • parenteral i.e., intramuscular, intravenous, subcutaneous, and nasal
  • compositions for effecting such treatment will contain a major or minor amount, e.g., from 95% to 0.5% of at least one compound of the present invention in combination with a pharmaceutical carrier, the carrier comprising one or more solid, semi-solid, or liquid diluents, fillers, and formulation adjuvants which are non-toxic, inert, and pharmaceutically acceptable.
  • a pharmaceutical carrier comprising one or more solid, semi-solid, or liquid diluents, fillers, and formulation adjuvants which are non-toxic, inert, and pharmaceutically acceptable.
  • Such pharmaceutical compositions are preferable in dosage unit form; i.e., physically discreet units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response.
  • Other therapeutic agents can also be present.
  • Pharmaceutical compositions providing from about 0.1 to 500 mg of the active
  • ingredient per unit dose are preferred and are selected.
  • oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, or
  • polyvinylpyrrolidone polyvinylpyrrolidone
  • fillers e.g., lactose, sugar, maize-starch, calcium phosphate, sorbitol, or glycine
  • lubricants e.g., magnesium stearate, talc, polyethylene glycol, or silica
  • disintegrants e.g., starch
  • wetting agents e.g., sodium lauryl sulfate.
  • Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are employed for parenteral compositions, such as an aqueous solution for intravenous injection or an oily suspension for intramuscular
  • compositions having the desired clarity, stability, and adaptability for parenteral use are obtained by dissolving from 0.1% to 10% by weight of the active compound in water or a vehicle consisting of a polyhydric aliphatic alcohol, such as glycerine,
  • polyethylene glycol consist of a mixture of non-volatile, usually liquid, polyethylene glycols which are soluble in both water and organic liquids and have molecular weights from about 200 to 1500.
  • another aspect of the instant invention concerns a method for treating HIV infections in mammals, including humans, in need of such treatment which comprises systemic or topical administration to such mammal of an effective dose of a Formula I compound or a pharmaceutically acceptable salt or solvate thereof.
  • a further aspect of the instant invention concerns a method for treating human cells infected with HIV infections which comprises systemic or topical administration to such cells of an effective dose of a Formula I compound or a pharmaceutically acceptable salt or solvate thereof.
  • an effective dose could be expected to be from about 0.001 to about 30 mg/kg body weight. It is envisioned that, for clinical antiviral application, compounds of the instant invention will be administered in the same manner and use as for the reference drugs AZT, DDI, and D4T.
  • a daily oral dose will comprise from about 0.1 to about 750 mg, preferably 10-500 mg of a Formula I compound administered from 1 to 3 times a day. In some instances, a sufficient amount of a Formula I compound administered from 1 to 3 times a day.
  • the dosage to be used in such a regimen may be adjusted with due consideration of factors listed above and to maintain serum drug level at an anti-HIV effective level.
  • TMS tetramethylsilane
  • Carbon-13 nuclear magnetic resonance ( 13 C NMR) spectra were recorded on a Bruker AM 300 or Varian Gemini 300 spectrometer and were broad band proton decoupled. All spectra were determined in CDCl 3 , DMSO-d 6 , or D 2 O unless otherwise indicated with internal deuterium lock, and chemical shifts are reported in units downfield from tetramethylsilane, relative to an internal standard.
  • IR Infrared
  • Optical rotations [ ⁇ ] 20 were determined on a Perkin-Elmer 41 polarimeter in the solvents indicated. Mass spectra were recorded on a Kratos MS-50 or a Finnegan 4500 instrument utilizing the fast atom bombardment (FAB) or direct chemical ionization (DCI) technique. The mass data are expressed in the format: protonated parent ion (MH + ).
  • Celite is a registered trademark of the Johns-Manvilie Products Corporation for
  • hexanes is a mixture of isomeric C 6 hydrocarbons as specified by the American Chemical Society, and the term "inert"
  • atmosphere is an argon or nitrogen atmosphere unless otherwise indicated.
  • the title compound can be prepared using the procedure of Example 8 but with the (S) chiral starting material.
  • Examples 4, 5, 6, 7, 8 and 9 can be prepared by reduction of the compounds of Examples 4-9.

Abstract

On décrit des dérivés acycliques alkényle et alkynyle de purine et de pyrimidine substitués par phosphonométhoxyalkyle et une composition pharmaceutique comprenant lesdits dérivés de purine et de pyrimidine. Ces composés sont utiles dans le traitement d'infections virales, surtout celles causées par le virus de l'immunodéficience humaine (VIH).
EP92922088A 1991-10-11 1992-10-09 Derives acycliques antiviraux alcenyle et alkynyle de purine et de pyrimidine substitues par phosphonomethoxyalkyle Expired - Lifetime EP0630381B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US77783591A 1991-10-11 1991-10-11
PCT/US1992/008686 WO1993007157A1 (fr) 1991-10-11 1992-10-09 Derives acycliques antiviraux alcenyle et alkynyle de purine et de pyrimidine substitues par phosphonomethoxyalkyle
US777835 2001-02-05

Publications (3)

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EP0630381A1 true EP0630381A1 (fr) 1994-12-28
EP0630381A4 EP0630381A4 (en) 1995-01-04
EP0630381B1 EP0630381B1 (fr) 1997-04-09

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US (1) US5696263A (fr)
EP (1) EP0630381B1 (fr)
JP (1) JP3497505B2 (fr)
KR (1) KR0184530B1 (fr)
AT (1) ATE151432T1 (fr)
AU (1) AU661347B2 (fr)
CA (1) CA2120743C (fr)
CZ (1) CZ287745B6 (fr)
DE (1) DE69218968T2 (fr)
HU (1) HU225970B1 (fr)
IL (1) IL103410A (fr)
NO (1) NO305518B1 (fr)
TW (1) TW371662B (fr)
WO (1) WO1993007157A1 (fr)

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WO2003002580A1 (fr) 2001-06-29 2003-01-09 Institute Of Organic Chemistry And Biochemistry Ofthe Academy Of Sciences Of The Czech Republic Nouveaux composes et methodes therapeutiques
WO2004111064A1 (fr) 2003-06-16 2004-12-23 Institute Of Organic Chemistry And Biochemistry, Academy Of Sciences Of The Czech Republic Composés de pyrimidine à groupes phosphonate, en tant qu'analogues nucleotidiques antiviraux
US7439350B2 (en) 1993-09-17 2008-10-21 Gilead Sciences, Inc. Nucleotide analogs
EP2308885A2 (fr) 2008-02-20 2011-04-13 Gilead Sciences, Inc. Nouveaux composés et procédés pour la thérapie

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US5817647A (en) * 1993-04-01 1998-10-06 Merrell Pharmaceuticals Inc. Unsaturated acetylene phosphonate derivatives of purines
EP0618214A1 (fr) * 1993-04-01 1994-10-05 Merrell Dow Pharmaceuticals Inc. Dérivés phosphonates insaturés de purines et de pyrimidines
IT1270008B (it) * 1994-09-23 1997-04-16 Ist Superiore Sanita Derivati purinici ed 8-azapurinici atti al trattamento terapeutico dell'aids
US5977061A (en) * 1995-04-21 1999-11-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic N6 - substituted nucleotide analagues and their use
US8586781B2 (en) 1998-04-02 2013-11-19 Mbc Pharma, Inc. Bone targeted therapeutics and methods of making and using the same
CN1291994C (zh) 2000-07-21 2006-12-27 吉里德科学公司 核苷酸膦酸酯类似物前药及其筛选和制备方法
KR101033290B1 (ko) * 2004-07-02 2011-05-09 주식회사 엘지생명과학 다이아이소프로필((1-(하이드록시메틸)-사이클로프로필)옥시)메틸포스포네이트의 새로운 제조 방법
FR2908133B1 (fr) 2006-11-08 2012-12-14 Centre Nat Rech Scient Nouveaux analogues de nucleotides comme molecules precurseurs d'antiviraux
RU2012106469A (ru) * 2009-08-27 2013-11-10 Ипифэни Байосаенсиз, Инк. Новые нуклеозидфонаты и аналоги
AU2012290089B2 (en) * 2011-08-01 2016-09-29 Mbc Pharma, Inc. Vitamin B6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates
WO2013095684A1 (fr) 2011-12-22 2013-06-27 Geron Corporation Analogues de guanine en tant que substrats de télomérase et affecteurs de la longueur de télomères

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US7439350B2 (en) 1993-09-17 2008-10-21 Gilead Sciences, Inc. Nucleotide analogs
WO2003002580A1 (fr) 2001-06-29 2003-01-09 Institute Of Organic Chemistry And Biochemistry Ofthe Academy Of Sciences Of The Czech Republic Nouveaux composes et methodes therapeutiques
WO2004111064A1 (fr) 2003-06-16 2004-12-23 Institute Of Organic Chemistry And Biochemistry, Academy Of Sciences Of The Czech Republic Composés de pyrimidine à groupes phosphonate, en tant qu'analogues nucleotidiques antiviraux
EP2308885A2 (fr) 2008-02-20 2011-04-13 Gilead Sciences, Inc. Nouveaux composés et procédés pour la thérapie

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ATE151432T1 (de) 1997-04-15
CA2120743C (fr) 2005-03-08
IL103410A (en) 1998-01-04
IL103410A0 (en) 1993-03-15
CA2120743A1 (fr) 1993-04-15
JPH07503453A (ja) 1995-04-13
NO305518B1 (no) 1999-06-14
DE69218968T2 (de) 1997-10-09
HU9401002D0 (en) 1994-07-28
NO941275D0 (no) 1994-04-08
TW371662B (en) 1999-10-11
AU661347B2 (en) 1995-07-20
KR0184530B1 (ko) 1999-05-15
HU225970B1 (en) 2008-01-28
US5696263A (en) 1997-12-09
CZ84594A3 (en) 1995-07-12
NO941275L (no) 1994-06-10
EP0630381A4 (en) 1995-01-04
CZ287745B6 (cs) 2001-01-17
DE69218968D1 (en) 1997-05-15
AU2783192A (en) 1993-05-03
HUT66770A (en) 1994-12-28
WO1993007157A1 (fr) 1993-04-15
EP0630381B1 (fr) 1997-04-09
JP3497505B2 (ja) 2004-02-16

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